5-(Acetyl-(3-(acetyl-(3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodophenyl)amino)-2- hydroxypropyl)amino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide; 5,5'-((2-Hydroxytrimethylene)bis(acetylimino))bis(N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodoisophthalamide);

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 1989 - January 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: United States Food and Drug Administration, Title 21 code of federal regultions part 58, federal register, 22 december 1978, and subsequent amendments.

Principles of method if other than guideline:

The test was conducted accoding to Methods for Administrering agents and detecting malformations in experimental animals - in Teratology: Prinsiples and Techniques. J.G. Wilson and J. Warkany Eds. University of Chicago Press, p 262-277

GLP compliance:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Duration of treatment / exposure:

Male: 9 weeks. pre mating + during mating Female : 2 weeks. pre mating + during mating + through day 7 gestation

Frequency of treatment:

Males were dosed 9 weeks prior to mating, and through mating to termination. Females were dosed from 2 weeks prior to mating until presumed day 7 of pregnancy. On day 20 of pregnancy, females were sacrificed, subjected to post mortem examination, during which kidney weights were recorded.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.094 other: ml / 100 g (320 mgI/ml)

Remarks:

Treatment Iodixanol 0.3 gI/kg/day, Female: 25

Doses / concentrations 2

Dose / conc.:

0.312 other: ml / 100 g (320 mgI/ml)

Remarks:

Treatment Iodixanol 1.0 gI/kg/day, Female: 25

Doses / concentrations 3

Dose / conc.:

0.625 other: ml / 100 g (320 mgI/ml)

Remarks:

Treatment Iodixanol 2.0 gI/kg/day, Female: 25

Control animals:

yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Effect levels (P0)

1

Dose descriptor:

NOEL

Effect level:

0.3 other: g I/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Maternal response

2

Dose descriptor:

NOEL

Effect level:

1 other: g I/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Maternal response

3

Dose descriptor:

NOEL

Effect level:

2 other: g I/kgbw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Maternal response

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

2 other: gI/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

organ weights and organ / body weight ratios

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Treatment with iodixanol had no apparent adverse effects on mating performance, pregnancy rate, copulation or fertility indices, litter parameters as assessed by pre- and post-implantation loss, litter size, sex ratio, or litter and mean foetal weight. Iodixanol did not produce any selective impairment of embryofoetal development or morphology as assessed by gross examination of foetuses on day 20 of pregnancy. The NOEL for maternal toxicity was determined to be 0.3 gI/kg/day, and >2 gI/kg/day for the developing conceptus.

Executive summary:

The potential effects of intravenously administered iodixanol on fertility and general reproductive performance have been studied in 28 male and 24 female rats at dosages of 0 (saline control), 0.3, 1.0 and 2.0 gI/kg/day. Males were dosed 9 weeks prior to mating, and through mating to termination. Females were dosed from 2 weeks prior to mating until presumed day 7 of pregnancy. On day 20 of pregnancy, females were sacrificed, subjected to post mortem examination, during which kidney weights were recorded. Litter values were determined and the foetuses were subjected to gross examination prior to preservation. Males were also subjected to post mortem examination and the kidneys weighed.

Treatment with iodixanol was associated with toxic effects in the parent animals, similar to those observed in rat repeated dose toxicity studies with iodixanol. Doses of 2.0 gI/kg/day was associated with transient reddening of extremities, urinary excretion of a clear sticky fluid, and swollen face and/or paws among the males, and in females, increased water and decreased food consumption, accompanied by lower weekly body weight and reduced weight gain during pregnancy. Kidney weights increased in both sexes. Treatment with 1.0 gI/kg/day was associated with occasional reddening of the extremities and swollen paws and face, increased water consumption, slightly decreased food consumption in males, and slightly reduced weight gain in females from day 14 of pregnancy. Kidney weights increased in males. Treatment with 0.3 gI/kg/day was associated with an increase in water consumption, and in males a slight decrease in mean food consumption and weekly body weight. Treatment with iodixanol had no apparent adverse effects on mating performance, pregnancy rate, copulation or fertility indices, litter parameters as assessed by pre- and post-implantation loss, litter size, sex ratio, or litter and mean foetal weight. Iodixanol did not produce any selective impairment of embryofoetal development or morphology as assessed by gross examination of foetuses on day 20 of pregnancy. The NOEL for maternal toxicity was determined to be 0.3 gI/kg/day, and >2 gI/kg/day for the developing conceptus.